Drugs such as aspirin, ibuprofen, acetaminophen, and morphine are used as analgesics. Ibuprofen, aspirin and other analgesic nonsteroidal anti-inflammatory drugs (commonly referred to as NSAIDs) and acetaminophen are only useful in relieving pain of moderate intensity, whereas opioid analgesics such as morphine are useful in relieving more intense pain. However, opioids exhibit side-effects including addictive properties, and ibuprofen, aspirin, other NSAIDs and acetaminophen can cause serious gastrointestinal, renal, and cardiovascular side effects, especially when used in high doses and/or over long periods of time.
NSAIDs, which are non-opioid analgesics, have been combined with other drugs, including opioid analgesic agents, in order to achieve an effective degree of analgesia with a lower dosage of NSAID and/or other analgesic compound. These combination products exhibit a variety of effects on the level of analgesia, which may be sub-additive (inhibitory), additive, or super-additive (synergistic). For example, U.S. Pat. No. 4,571,400 discloses that the combination of dihydrocodeine (an opioid analgesic) and ibuprofen (an NSAID) provides super-additive analgesia when the components are combined within certain ratios. A. Pircio et al., Arch. Int. Pharmacodyn., 235,116 (1978) report that a mixture of butorphanol (an opioid analgesic) with acetaminophen (a non-opioid analgesic) in a 1:125 ratio yielded super-additive analgesia, but that a 1:10 mixture of the same components yielded merely additive analgesic effects. A combination of tolmetin (an NSAID) with acetaminophen (a non-opioid analgesic) has been reported to enable a marked reduction in the amount of tolmetin required to produce analgesia (G. Stacher et al., Int. J. Clin. Pharmacol. Biopharmacy, 17, 250 (1977)). However, it is also known that the daily consumption of non-opioid analgesics, either alone or in combination, in large amounts or over time also poses health risks. Moreover, it is known that the effects on the level of analgesia obtained when combining such analgesics is highly unpredictable, depending on the choice of analgesics combined and the ratios at which they are combined. Specifically, a particular combination may provide a sub-additive level of analgesia.
Glucosamine is an essential intermediate in the biosynthetic pathway of proteoglycans, which are the primary building blocks of connective tissue and cartilage. Glucosamine compounds exhibit weak anti-inflammatory activity, but no analgesic activity. Glucosamine in combination with manganese and chondroitin, which is also a component of proteoglycans, is currently marketed as a nutritional supplement to enhance the repair and synthesis of connective tissue and cartilage (See U.S. Pat. Nos. 5,364,845; 5,587,363; 5,840,715). Glucosamine combined with ascorbic acid, tyrosine or phenylalanine, and calcium has been shown to accelerate wound healing (See U.S. Pat. Nos. 4,647,453; 4,772,591; and 5,679,344). Glucosamine has also been used to improve the solubility of NSAIDs by combining a glucosamine with an NSAID in a 1:1 molar ratio to form a glucosamine salt or complex with the NSAID, but the analgesic effect (whether sub-additive, additive or synergistic) has not been reported for these complexes (See U.S. Pat. Nos. 4,501,727; 5,604,206; and 6,069,172). In addition, aspirin plus glucosamine has been disclosed in U.S. Pat. No. 3,008,874 to enhance the blood level of aspirin, specifically at glucosamine to aspirin weight ratios of 0.25:1 and 0.77:1. As with the prior art cited above relating to glucosamine: NSAID complexes, there is no disclosure of the analgesic effect of these compositions.
Numerous studies have compared the pain relief achieved in arthritic conditions from the use of glucosamine with the pain relief achieved with various analgesic compounds alone, but there has been no suggestion to use glucosamine and an analgesic compound of this invention together in order to obtain additive or super-additive analgesia. To the contrary, the scientific literature uniformly emphasizes the need to replace NSAIDs with glucosamine, while the marketing of glucosamine products most often emphasizes that the product does not contain analgesic. Further to the contrary, it has been shown that when glucosamine is combined at certain ratios, for example with aspirin, diclofenac or tramadol (a centrally acting non-opioid analgesic), the analgesic efficacy of analgesic is reduced (i.e., the combination is sub-additive) by as much as 80%, as discussed below. Accordingly, one skilled in the art cannot predict whether a combination of glucosamine with an analgesic will produce sub-additive analgesia, additive analgesia, or super-additive analgesia.
Nevertheless, a need exists to both decrease the side effects and enhance the analgesic effects of analgesics such as opioids, non-opioid analgesics, and NSAIDs. The object of the present invention is to combine glucosamine with a therapeutic amount of an analgesic compound to provide an analgesic composition which provides analgesia at least equal to and in many cases substantially greater than that of the analgesic compound alone. In the preferred embodiments of this invention the analgesic compound and the ratio of glucosamine to analgesic compound are selected to avoid significant sub-additive analgesic effects which can occur when two or more analgesics are combined or when an analgesic, such as diclofenac or tramadol, is combined with glucosamine. In the preferred embodiment, the combination of glucosamine with an analgesic compound at an appropriate ratio will synergistically enhance the analgesic effect of the analgesic compound, such as an NSAID, so that less analgesic compound is needed to produce effective analgesia, and potential side-effects are accordingly reduced. In addition the combination of glucosamine with an analgesic is also expected to retain its beneficial effects on restoration and maintenance of cartilage.